Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.

Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Adults with metabolically healthy overweight or obesity present more brown adipose tissue and higher thermogenesis than their metabolically unhealthy counterparts.

BACKGROUND: There is a subset of individuals with overweight/obesity characterized by a lower risk of cardiometabolic complications, the so-called metabolically healthy overweight/obesity (MHOO) phenotype. Despite the relatively higher levels of subcutaneous adipose tissue and lower visceral adipose tissue observed in individuals with MHOO than individuals with metabolically unhealthy overweight/obesity (MUOO), little is known about the differences in brown adipose tissue (BAT). METHODS: This study included 53 young adults (28 women) with a body mass index (BMI) ≥25 kg/m2 which were classified as MHOO (n = 34) or MUOO (n = 19). BAT was assessed through a static 18F-FDG positron emission tomography/computed tomography scan after a 2-h personalized cooling protocol. Energy expenditure, skin temperature, and thermal perception were assessed during a standardized mixed meal test (3.5 h) and a 1-h personalized cold exposure. Body composition was assessed by dual-energy x-ray absorptiometry, energy intake was determined during an ad libitum meal test and dietary recalls, and physical activity levels were determined by a wrist-worn accelerometer. FINDINGS: Participants with MHOO presented higher BAT volume (+124%, P = 0.008), SUVmean (+63%, P = 0.001), and SUVpeak (+133%, P = 0.003) than MUOO, despite having similar BAT mean radiodensity (P = 0.354). In addition, individuals with MHOO exhibited marginally higher meal-induced thermogenesis (P = 0.096) and cold-induced thermogenesis (+158%, P = 0.050). Moreover, MHOO participants showed higher supraclavicular skin temperature than MUOO during the first hour of the postprandial period and during the cold exposure, while no statistically significant differences were observed in other skin temperature parameters. We observed no statistically significant differences between MHOO and MUOO in thermal perception, body composition, outdoor ambient temperature exposure, resting metabolic rate, energy intake, or physical activity levels. INTERPRETATION: Adults with MHOO present higher BAT volume and activity than MUOO. The higher meal- and cold-induced thermogenesis and cold-induced supraclavicular skin temperature are compatible with a higher BAT activity. Overall, these results suggest that BAT presence and activity might be linked to a healthier phenotype in young adults with overweight or obesity. FUNDING: See acknowledgments section.

Sex-specific dose-response effects of a 24-week supervised concurrent exercise intervention on cardiorespiratory fitness and muscular strength in young adults: The ACTIBATE randomized controlled trial.

Concurrent training has been postulated as an appropriate time-efficient strategy to improve physical fitness, yet whether the exercise-induced adaptations are similar in men and women is unknown. An unblinded randomized controlled trial was conducted to investigate sex-specific dose-response effects of a 24-week supervised concurrent exercise training program on cardiorespiratory fitness and muscular strength in young adults. One hundred and forty-four sedentary adults aged 18-25 years were assigned to either (i) a control group (n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 46), or (iii) a vigorous intensity exercise group (VIG-EX, n = 44) by unrestricted randomization. Cardiorespiratory fitness (VO2max ), hand grip strength, and one-repetition maximum of leg press and bench press were evaluated at baseline and after the intervention. A total of 102 participants finished the intervention (Control, n = 36; 52% women, MOD-EX, n = 37; 70% women, and VIG-EX, n = 36; 72% women). In men, VO2max significantly increased in the MOD-EX (~8%) compared with the control group and in the VIG-EX group after the intervention (~6.5%). In women, VO2max increased in the MOD-EX and VIG-EX groups (~5.5%) compared with the control group after the intervention. There was a significant increment of leg press in the MOD-EX (~15.5%) and VIG-EX (~18%) groups compared with the control group (~1%) in women. A 24-week supervised concurrent exercise was effective at improving cardiorespiratory fitness and lower body limbs muscular strength in young women-independently of the predetermined intensity-while only at moderate intensity improved cardiorespiratory fitness in men.

Higher plasma levels of endocannabinoids and analogues correlate with a worse cardiometabolic profile in young adults.

BACKGROUND AND AIM: The endocannabinoid system is a signalling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the ECS are linked to the development of cardiometabolic diseases. Here, we investigated the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors. METHODS: The study included 133 young adults (age 22.1 ± 2.2 years, 67% women). Fasting plasma levels of eCBs and their analogues were measured using liquid chromatography-tandem mass spectrometry. Body composition, brown adipose tissue (BAT) volume, glucose uptake, and traditional cardiometabolic risk factors were measured. RESULTS: Plasma levels of eCBs and several eCB analogues were positively correlated with adiposity and traditional cardiometabolic risk factors (e.g., serum insulin and triacylglycerides levels, all r ≥ 0.17 and p ≤ 0.045). Plasma levels of 2-AG and PDEA were negatively correlated with BAT volume and glucose uptake (all r ≤ -0.17 and P ≤ 0.047). We observed that the plasma levels of eCBs and their analogues were higher in metabolically unhealthy overweight-obese participants than in metabolically healthy overweight-obese participants. CONCLUSION: Our findings show that the plasma levels of eCBs and their analogues are related to higher levels of adiposity and worse cardiometabolic profile.

Thermal resting pattern and acute skin temperature response to exercise in older adults: Role of cardiorespiratory fitness.

BACKGROUND: Infrared thermography is a growing area of interest in sports science due to the potential of skin temperature (Tsk) measurements to provide valuable information from rest to exercise. However, limited research exists on Tsk in older adults and the impact of factors such as sex and cardiorespiratory fitness (CRF) on Tsk. This study aims to investigate Tsk at rest and after acute exercise in older adults and assess whether sex or CRF influences Tsk. METHODS: Ninety-two participants (41 women, 68.48 ± 3.01 years) were examined with a thermographic camera in a conditioned room (23.02 ± 3.01 °C) at rest and after a graded protocol. The Tsk of 25 regions of interest (ROIs) were extracted and analysed. RESULTS: Men had higher overall Tsk at rest in 76% of ROIs, showing significant differences (p < 0.010) in six specific ROIs, independent of CRF. Both sexes had similar Tsk responses after graded exercise, with increases in distal parts (1.06 ± 0.50 °C), decreases in proximal parts (-0.62 ± 0.42 °C), and stable central Tsk (0.23 ± 0.59 °C). Increases in lower limb Tsk were significantly associated with CRF in men and women (ß = 0.438, p = 0.001, and ß = 0.535, p < 0.001, respectively), explaining 17% and 27% of the variance, respectively. CONCLUSIONS: This study demonstrates a sex-specific effect on resting Tsk in older adults, suggesting that sex-specific Tsk patterns should be considered when analysing Tsk in this population. Additionally, the association between increases in lower limb Tsk and CRF suggests that Tsk could be a promising predictor of CRF in older adults.

Effect of a 24-Week Concurrent Exercise Intervention on Neck Adiposity and Its Distribution in Young Adults: The ACTIBATE Randomized Controlled Trial.

Neck adipose tissue (NAT) accumulation and neck circumference are independent predictors of cardiometabolic risk (CMR) and low-grade chronic inflammation in young adults. The present study examines whether a 24-week concurrent exercise intervention can reduce NAT volume and neck circumference in young adults, and whether any changes in these variables are related to changes in body composition, CMR, and the inflammatory profile. Seventy-four participants (51 women, age 22 ± 2 years) were included in the main analyses, after being randomly assigned to either a (a) control (n = 34), (b) moderate-intensity exercise (n = 19), or (c) vigorous-intensity exercise (n = 21) group. Participants in the exercise groups trained 3-4 days/week (endurance + resistance exercise training). NAT volume and NAT distribution across different depots were estimated using computed tomography before and after the intervention. Anthropometric variables, body composition (determined by dual-energy X-ray absorptiometry), and CMR/inflammatory markers were also recorded. The exercise intervention did not reduce the total NAT volume, nor was NAT distribution affected (p > .05). However, it did reduce neck circumference in the vigorous-intensity exercise group compared with the moderate-intensity exercise and control groups (by 0.8 and 1 cm, respectively, p ≤ .05). Changes in total NAT and neck circumference were positively, albeit weakly, related (adj. R2: .05-.21, all p ≤ .05) to changes in body weight and adiposity, leptin (only total NAT), and CMR (only neck circumference). Altogether 24 weeks of concurrent exercise does not appear to reduce NAT accumulation in young adults, but may slightly reduce neck circumference in those who partake in vigorous exercise.

The relative abundance of fecal bacterial species belonging to the Firmicutes and Bacteroidetes phyla is related to plasma levels of bile acids in young adults.

BACKGROUND: Gut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly understood. Here, we investigated the relationship between fecal microbiota diversity and composition with plasma levels of BA in young adults. METHODS: Fecal microbiota diversity/composition was analyzed with 16S rRNA sequencing in 80 young adults (74% women; 21.9 ± 2.2 years old). Plasma levels of BA were measured using liquid chromatography-tandem mass spectrometry. PERMANOVA and Spearman correlation analyses were used to investigate the association between fecal microbiota parameters and plasma levels of BA. RESULTS: Fecal microbiota beta (P = 0.025) and alpha diversity indexes of evenness (rho = 0.237, P = 0.033), Shannon (rho = 0.313, P = 0.004), and inverse Simpson (rho = 0.283, P = 0.010) were positively associated with plasma levels of the secondary BA glycolithocholic acid (GLCA). The relative abundance of genera belonging to the Firmicutes and Bacteroidetes phyla was positively correlated with plasma levels of GLCA (all rho ≥ 0.225, P ≤ 0.049). However, the relative abundance of species from Firmicutes and Bacteroidetes phyla were negatively correlated with plasma levels of primary and secondary BA (all rho ≤ - 0.220, P ≤ 0.045), except for the relative abundance of Bacteroides vulgatus, Alistipes onderdonkii, and Bacteroides xylanisolvens species (Bacteroidetes phylum) that were positively correlated with the plasma levels of GLCA. CONCLUSIONS: The relative abundance of specific fecal bacteria species is associated with plasma levels of BA in young adults. However, further investigations are required to validate whether the composition of the gut microbiota can regulate the plasma concentrations of BA in humans.

A bout of endurance and resistance exercise transiently decreases plasma levels of bile acids in young, sedentary adults.

Circulating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here, we evaluate the effects of a bout of maximal endurance exercise (EE) and resistance exercise (RE) on plasma levels of BA in young, sedentary adults. Concentration of eight plasma BA was measured by liquid chromatography-tandem mass spectrometry before and 3, 30, 60, and 120 min after each exercise bout. Cardiorespiratory fitness (CRF) was assessed in 14 young adults (21.8 ± 2.5 yo, 12 women); muscle strength was assessed in 17 young adults (22.4 ± 2.5 yo, 11 women). EE transiently decreased plasma levels of total, primary, and secondary BA at 3 and 30 min after exercise. RE exerted a prolonged reduction in plasma levels of secondary BA (p < 0.001) that lasted until 120 min. Primary BA levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) were different across individuals with low/high CRF levels after EE (p ≤ 0.044); CA levels were different across individuals with low/high handgrip strength levels. High CRF individuals presented higher levels of CA and CDCA 120 min after exercise vs baseline (+77% and +65%) vs the low CRF group (-5% and -39%). High handgrip strength levels individuals presented higher levels of CA 120 min after exercise versus baseline (+63%) versus the low handgrip strength group (+6%). The study findings indicate that an individual's level of physical fitness can influence how circulating BA respond to both endurance and resistance exercise. Additionally, the study suggests that changes in plasma BA levels after exercising could be related to the control of glucose homeostasis in humans.

Image registration and mutual thresholding enable low interimage variability across dynamic MRI measurements of supraclavicular brown adipose tissue during mild cold exposure.

PURPOSE: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising noninvasive measure to assess BAT activity but suffers from high scan variability. We aimed to test the effects of coregistration and mutual thresholding on the scan variability in a fast (1 min) time-resolution MRI protocol for assessing scBAT FF changes during cold exposure. METHODS: Ten volunteers (age 24.8 ± 3.0 years; body mass index 21.2 ± 2.1 kg/m2 ) were scanned during thermoneutrality (32°C; 10 min) and mild cold exposure (18°C; 60 min) using a 12-point gradient-echo sequence (70 consecutive scans with breath-holds, 1.03 min per dynamic). Dynamics were coregistered to the first thermoneutral scan, which enabled drawing of single regions of interest in the scBAT depot. Voxel-wise FF changes were calculated at each time point and averaged across regions of interest. We applied mutual FF thresholding, in which voxels were included if their FF was greater than 30% FF in the reference scan and the registered dynamic. The efficacy of the coregistration was determined by using a moving average and comparing the mean squared error of residuals between registered and nonregistered data. Registered scBAT ΔFF was compared with single-scan thresholding using the moving average method. RESULTS: Registered scBAT ΔFF had lower mean square error values than nonregistered data (0.07 ± 0.05% vs. 0.16 ± 0.14%; p < 0.05), and mutual thresholding reduced the scBAT ΔFF variability by 30%. CONCLUSION: We demonstrate that coregistration and mutual thresholding improve stability of the data 2-fold, enabling assessment of small changes in FF following cold exposure.

Acute Mechanical and Skin Temperature Responses to Different Interrepetition Rest Intervals During Full-Squat Exercise.

PURPOSE: This study aimed to (1) evaluate the acute effects of different interrepetition rest full-squat protocols on countermovement jump (CMJ) height, velocity loss (VL), and skin temperature (Tsk) and (2) determine whether the VL, the changes in Tsk, or the individual strength level is associated with the change in CMJ height. METHODS: Sixteen resistance-trained men randomly performed 3 squat protocols at maximal intended velocity with 60% of the 1-repetition maximum (sets × repetitions [interrepetition rest]): traditional (2 × 6 [0 s]), cluster 2 (2 × 6 [30 s every 2 repetitions]), and cluster 1 (1 × 12; [36 s every repetition]), plus a control session. CMJ height was assessed before and 2, 4, and 8 minutes after the protocols. RESULTS: There was a significant main effect of protocol for the VL (F = 20.54, P < .001) and loss in mean power (F = 12.85, P < .001; traditional > cluster 2 > cluster 1). However, we found a comparable reduction of CMJ height after 8 minutes: traditional (-3.4% [4.2%]), cluster 2 (-5.3% [4.9%]), cluster 1 (-5.4% [2.9%]), and control (-4.2% [3.6%]). Overall, mean Tsk acutely decreased after all the protocols. Higher individual strength level (but not VL or the changes in Tsk) was associated with lower CMJ-height loss (P < .05). CONCLUSIONS: Although different interrepetition rest full-squat protocols may alter the loss in velocity and power, they result in a similar decrease in Tsk and CMJ height, which could be more influenced by individual strength level than VL or changes in Tsk.

High omega-6/omega-3 fatty acid and oxylipin ratio in plasma is linked to an adverse cardiometabolic profile in middle-aged adults.

Omega-6 and omega-3 oxylipins may be surrogate markers of systemic inflammation, which is one of the triggers for the development of cardiometabolic disorders. In the current study, we investigated the relationship between plasma levels of omega-6 and omega-3 oxylipins with body composition and cardiometabolic risk factors in middle-aged adults. Seventy-two 72 middle-aged adults (39 women; 53.6±5.1 years old; 26.7±3.8 kg/m2) were included in this cross-sectional study. Plasma levels of omega-6 and omega-3 fatty acids and oxylipins were determined using targeted lipidomic. Body composition, dietary intake, and cardiometabolic risk factors were assessed with standard methods. The plasma levels of the omega-6 fatty acids and derived oxylipins, the hydroxyeicosatetraenoic acids (HETEs; arachidonic acid (AA)-derived oxylipins) and dihydroxy-eicosatrienoic acids (DiHETrEs; AA-derived oxylipins), were positively associated with glucose metabolism parameters (i.e., insulin levels and homeostatic model assessment of insulin resistance index (HOMA); all r≥0.21, P<.05). In contrast, plasma levels of omega-3 fatty acids and derived oxylipins, specifically hydroxyeicosapentaenoic acids (HEPEs; eicosapentaenoic acid-derived oxylipins), as well as series-3 prostaglandins, were negatively associated with plasma glucose metabolism parameters (i.e., insulin levels, HOMA; all r≤0.20, P<.05). The plasma levels of omega-6 fatty acids and derived oxylipins, HETEs and DiHETrEs were also positively correlated with liver function parameters (i.e., glutamic pyruvic transaminase, gamma-glutamyl transferase (GGT), and fatty liver index; all r≥0.22 and P<.05). In addition, individuals with higher omega-6/omega-3 fatty acid and oxylipin ratio showed higher levels of HOMA, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and GGT (on average +36%), as well as lower levels of high-density lipoprotein cholesterol (-13%) (all P<.05). In conclusion, the omega-6/omega-3 fatty acid and oxylipin ratio, as well as specific omega-6 and omega-3 oxylipins plasma levels, reflect an adverse cardiometabolic profile in terms of higher insulin resistance and impaired liver function in middle-aged adults.

Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue.

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).

Exercise-induced changes on exerkines that might influence brown adipose tissue metabolism in young sedentary adults.

ABSTRACTIn rodents, exercise alters the plasma concentration of exerkines that regulate white adipose tissue (WAT) browning or brown adipose tissue (BAT) metabolism. This study aims to analyse the acute and chronic effect of exercise on the circulating concentrations of 16 of these exerkines in humans. Ten young sedentary adults (6 female) performed a maximum walking effort test and a resistance exercise session. The plasma concentration of 16 exerkines was assessed before, and 3, 30, 60, and 120 min after exercise. Those exerkines modified by exercise were additionally measured in another 28 subjects (22 women). We also measured the plasma concentrations of the exerkines before and after a 24-week exercise programme (endurance + resistance; 3-groups: control, moderate-intensity and vigorous-intensity) in 110 subjects (75 women). Endurance exercise acutely increased the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, and follistatin-like protein 1 (3 min after exercise), and musclin and fibroblast growth factor 21 (30 and 60 min after exercise), decreasing the plasma concentration of leptin (30 min after exercise). Adiponectin, atrial natriuretic peptide (ANP), ß-aminoisobutyric acid, meteorin-like, follistatin, pro-ANP, irisin and myostatin were not modified or not detectable. The resistance exercise session increased the plasma concentration of lactate 3 min after exercise. Chronic exercise did not alter the plasma concentration of these exerkines. In sedentary young adults, acute endurance exercise releases to the bloodstream exerkines that regulate BAT metabolism and WAT browning. In contrast, neither a low-volume resistance exercise session nor a 24-week training programme modified plasma levels of these molecules.HighlightsAcute endurance exercise increases the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, follistatin-like protein 1, musclin, and fibroblast growth factor 21, and decrease the plasma concentration of leptin.The exercise-induced change in lactate plasma concentration is positively associated with brown adipose tissue volume, glucose uptake and radiodensity.Neither acute resistance exercise nor chronic exercise significantly alter the plasma concentration of these exerkines.Trial registration: ClinicalTrials.gov identifier: NCT02365129.

Differences in Inflammatory Pathways Between Dutch South Asians vs Dutch Europids With Type 2 Diabetes.

CONTEXT: South Asian individuals are more prone to develop type 2 diabetes (T2D) coinciding with earlier complications than Europids. While inflammation plays a central role in the development and progression of T2D, this factor is still underexplored in South Asians. OBJECTIVE: This work aimed to study whether circulating messenger RNA (mRNA) transcripts of immune genes are different between South Asian compared with Europid patients with T2D. METHODS: A secondary analysis was conducted of 2 randomized controlled trials of Dutch South Asian (n = 45; age: 55 ± 10 years, body mass index [BMI]: 29 ± 4 kg/m2) and Dutch Europid (n = 44; age: 60 ± 7 years, BMI: 32 ± 4 kg/m2) patients with T2D. Main outcome measures included mRNA transcripts of 182 immune genes (microfluidic quantitative polymerase chain reaction; Fluidigm Inc) in fasted whole-blood, ingenuity pathway analyses (Qiagen). RESULTS: South Asians, compared to Europids, had higher mRNA levels of B-cell markers (CD19, CD79A, CD79B, CR2, CXCR5, IGHD, MS4A1, PAX5; all fold change > 1.3, false discovery rate [FDR] < 0.008) and interferon (IFN)-signaling genes (CD274, GBP1, GBP2, GBP5, FCGR1A/B/CP, IFI16, IFIT3, IFITM1, IFITM3, TAP1; all FC > 1.2, FDR < 0.05). In South Asians, the IFN signaling pathway was the top canonical pathway (z score 2.6; P < .001) and this was accompanied by higher plasma IFN-γ levels (FC = 1.5, FDR = 0.01). Notably, the ethnic difference in gene expression was larger for women (20/182 [11%]) than men (2/182 [1%]). CONCLUSION: South Asian patients with T2D show a more activated IFN-signaling pathway compared to Europid patients with T2D, which is more pronounced in women than men. We speculate that a more activated IFN-signaling pathway may contribute to the more rapid progression of T2D in South Asian compared with Europid individuals.

Plasma Levels of Omega-3 and Omega-6 Derived Oxylipins Are Associated with Fecal Microbiota Composition in Young Adults.

Pre-clinical studies suggest that circulating oxylipins, i.e., the oxidation products of polyunsaturated fatty acids (PUFAs), modulate gut microbiota composition in mice, but there is no information available in humans. Therefore, this study aimed to investigate the relationship between omega-3 and omega-6 derived oxylipins plasma levels and fecal microbiota composition in a cohort of young adults. 80 young adults (74% women; 21.9 ± 2.2 years old) were included in this cross-sectional study. Plasma levels of oxylipins were measured using liquid chromatography-tandem mass spectrometry. Fecal microbiota composition was analyzed by V3-V4 16S rRNA gene sequencing. We observed that plasma levels of omega-3 derived oxylipins were positively associated with the relative abundance of Clostridium cluster IV genus (Firmicutes phylum; rho ≥ 0.415, p ≤ 0.009) and negatively associated with the relative abundance of Sutterella genus (Proteobacteria phylum; rho ≥ -0.270, p ≤ 0.041), respectively. Moreover, plasma levels of omega-6 derived oxylipins were negatively associated with the relative abundance of Acidaminococcus and Phascolarctobacterium genera (Firmicutes phylum; all rho ≥ -0.263, p ≤ 0.024), as well as Sutterella, Succinivibrio, and Gemmiger genera (Proteobacteria phylum; all rho ≥ -0.263, p ≤ 0.024). Lastly, the ratio between omega-6 and omega-3 oxylipins plasma levels was negatively associated with the relative abundance of Clostridium cluster IV genus (Firmicutes phylum; rho = -0.334, p = 0.004) and Butyricimonas genus (Bacteroidetes phylum; rho = -0.292, p = 0.014). In conclusion, our results show that the plasma levels of omega-3 and omega-6 derived oxylipins are associated with the relative abundance of specific fecal bacteria genera.

The Infrared Thermography Toolbox: An Open-access Semi-automated Segmentation Tool for Extracting Skin Temperatures in the Thoracic Region including Supraclavicular Brown Adipose Tissue.

Infrared thermography (IRT) is widely used to assess skin temperature in response to physiological changes. Yet, it remains challenging to standardize skin temperature measurements over repeated datasets. We developed an open-access semi-automated segmentation tool (the IRT-toolbox) for measuring skin temperatures in the thoracic area to estimate supraclavicular brown adipose tissue (scBAT) activity, and compared it to manual segmentations. The IRT-toolbox, designed in Python, consisted of image pre-alignment and non-rigid image registration. The toolbox was tested using datasets of 10 individuals (BMI = 22.1 ± 2.1 kg/m2, age = 22.0 ± 3.7 years) who underwent two cooling procedures, yielding four images per individual. Regions of interest (ROIs) were delineated by two raters in the scBAT and deltoid areas on baseline images. The toolbox enabled direct transfer of baseline ROIs to the registered follow-up images. For comparison, both raters also manually drew ROIs in all follow-up images. Spatial ROI overlap between methods and raters was determined using the Dice coefficient. Mean bias and 95% limits of agreement in mean skin temperature between methods and raters were assessed using Bland-Altman analyses. ROI delineation time was four times faster with the IRT-toolbox (01:04 min) than with manual delineations (04:12 min). In both anatomical areas, there was a large variability in ROI placement between methods. Yet, relatively small skin temperature differences were found between methods (scBAT: 0.10 °C, 95%LoA[-0.13 to 0.33 °C] and deltoid: 0.05 °C, 95%LoA[-0.46 to 0.55 °C]). The variability in skin temperature between raters was comparable between methods. The IRT-toolbox enables faster ROI delineations, while maintaining inter-user reliability compared to manual delineations. (Trial registration number (ClinicalTrials.gov): NCT04406922, [May 29, 2020]).

Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans.

The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (- 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (- 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (ß: 0.44, 95% CI [0.06-0.81], P = 0.024) after adjusting for study design but not BAT volume (ß: 0.39, 95% CI [- 0.01-0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.

Cold exposure induces dynamic changes in circulating triacylglycerol species, which is dependent on intracellular lipolysis: A randomized cross-over trial.

BACKGROUND: The application of cold exposure has emerged as an approach to enhance whole-body lipid catabolism. The global effect of cold exposure on the lipidome in humans has been reported with mixed results depending on intensity and duration of cold. METHODS: This secondary study was based on data from a previous randomized cross-over trial (ClinicalTrials.gov ID: NCT03012113). We performed sequential lipidomic profiling in serum during 120 min cold exposure of human volunteers. Next, the intracellular lipolysis was blocked in mice (eighteen 10-week-old male wild-type mice C57BL/6J) using a small-molecule inhibitor of adipose triglyceride lipase (ATGL; Atglistatin), and mice were exposed to cold for a similar duration. The quantitative lipidomic profiling was assessed in-depth using the Lipidyzer platform. FINDINGS: In humans, cold exposure gradually increased circulating free fatty acids reaching a maximum at 60 min, and transiently decreased total triacylglycerols (TAGs) only at 30 min. A broad range of TAG species was initially decreased, in particular unsaturated and polyunsaturated TAG species with ≤5 double bonds, while after 120 min a significant increase was observed for polyunsaturated TAG species with ≥6 double bonds in humans. The mechanistic study in mice revealed that the cold-induced increase in polyunsaturated TAGs was largely prevented by blocking adipose triglyceride lipase. INTERPRETATION: We interpret these findings as that cold exposure feeds thermogenic tissues with TAG-derived fatty acids for combustion, resulting in a decrease of circulating TAG species, followed by increased hepatic production of polyunsaturated TAG species induced by liberation of free fatty acids stemming from adipose tissue. FUNDING: This work was supported by the Netherlands CardioVascular Research Initiative: 'the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences' [CVON2017-20 GENIUS-II] to Patrick C.N. Rensen. Borja Martinez-Tellez is supported by individual postdoctoral grant from the Fundación Alfonso Martin Escudero and by a Maria Zambrano fellowship by the Ministerio de Universidades y la Unión Europea - NextGenerationEU (RR_C_2021_04). Lucas Jurado-Fasoli was supported by an individual pre-doctoral grant from the Spanish Ministry of Education (FPU19/01609) and with an Albert Renold Travel Fellowship from the European Foundation for the Study of Diabetes (EFSD). Martin Giera was partially supported by NWO XOmics project #184.034.019.

Acute and long-term exercise differently modulate plasma levels of oxylipins, endocannabinoids, and their analogues in young sedentary adults: A sub-study and secondary analyses from the ACTIBATE randomized controlled-trial.

BACKGROUND: Fatty acid-derived lipid mediators including oxylipins, endocannabinoids (eCBs), and their analogues, have emerged as key metabolites in the inflammatory and immune response to physiological stressors. METHODS: This report was based on a sub-study and secondary analyses the ACTIBATE single-center unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129). The study was performed in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada. Eligible participants were young, sedentary adults with no chronic diseases. Here, we performed both an acute endurance and resistance exercise sub-studies (n.ß=.ß14 and 17 respectively), and a 24-week supervised exercise intervention, combining endurance and resistance exercise training at moderate-intensity (MOD-EX) or vigorous-intensity (VIG-EX) exercise groups, in young sedentary adults. Randomization was performed by unrestricted randomization. Plasma levels of oxylipins, eCBs, and their analogues were measured using liquid chromatography-tandem mass spectrometry. FINDINGS: Both endurance and resistance exercise increased by.ß+50% the plasma levels of dihomo-..-linolenic acid and arachidonic acid (AA) omega-6 derived oxylipins, as well as eicosapentaenoic acid and docosahexaenoic acid omega-3 derived after 3 and 120.ßmin of the bout of exercise (all ..2.ß....ß0.219 and P.ß..±.ß0.039). These exercise modalities also increased the levels of anandamide and eCBs analogues (+25%). 145 young sedentary adults were assigned to a control (CON, n.ß=.ß54), a MOD-EX (n.ß=.ß48) or a VIG-EX (n.ß=.ß43). 102 participants were included in the final long-term analyses (CON, n.ß=.ß36; MOD-EX, n.ß=.ß33; and VIG-EX, n.ß=.ß33) of the trial. After 24-week of supervised exercise, MOD-EX decreased plasma levels of omega-6 oxylipins, concretely linoleic acid (LA) and adrenic acid derived oxylipins, and the eCBs analogues OEA and LEA in comparison to the CON (all P.ß..±.ß0.021). VIG-EX decreased LA-derived oxylipins and LEA compared to CON. No relevant adverse events were recorded. INTERPRETATION: Endurance and resistance exercises acutely increased plasma levels of oxylipins, eCBs, and their analogues, whereas 24 weeks of exercise training decreased fasting plasma levels of omega-6 oxylipins, and eCBs analogues in young, sedentary adults. FUNDING: See Acknowledgments section.